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Biomedical subjects

Peter W Mathieson

Publications and source records attributed to Peter W Mathieson.

26 records · Page 2Linked to original sources
PubMed2003

Immune dysregulation in minimal change nephropathy.

Minimal change nephropathy (MCN) has been associated with a wide variety of abnormalities in the immune response of affected individuals. Many of these may be a consequence of the renal lesion, rather than a cause thereof. This article reviews some of these immunological phenomena and concentrates in particular on the imbalance between type 1 and type 2 cytokine responses, suggesting that there are plausible mechanisms whereby a type 2 cytokine bias could directly or indirectly cause MCN.

Humans↗
PubMed2002

Effector mechanisms in murine allograft rejection: comparison of skin and heart grafts in fully allogeneic and minor histocompatibility antigen-mismatched strain combinations.

Cytotoxic T lymphocytes (CTLs) and macrophage-mediated delayed-type hypersensitivity (DTH) responses may both mediate allograft rejection. Furthermore, although allograft rejection is classically considered a type [22, 23, 38, 50, 52] 1 cellular immune response, type-2 cytokines can support rejection. This study examines whether the immunogenicity of the transplanted tissue, as determined by type of tissue (skin versus heart) and degree of antigenic mismatch, influences recruitment of these effector mechanisms. Graft survival, histological appearance and intragraft gene expression (IL-2, IFN-gamma, IL-12 p40, IL-4, IL-10, perforin, Fas ligand (Fas L), iNOS and TNF-alpha) were compared for fully allogeneic, minor histocompatibility (mHC) antigen-mismatched and syngeneic skin and heart grafts. We found mRNA characteristic of CTLs and DTH responses in fully allogeneic and mHC antigen-mismatched skin and heart grafts. Concomitant type-1 and type-2 cytokine gene transcription was seen. These findings demonstrate that the tissue grafted and degree of antigenic disparity between donor and recipient do not restrict the repertoire of cellular immune responses involved in graft rejection. This finding has implications in the design of new immunosuppressive strategies for clinical transplantation.

Animals↗
PubMed2002

Co-localization of nephrin, podocin, and the actin cytoskeleton: evidence for a role in podocyte foot process formation.

The discovery of the genes for nephrin and podocin, which are mutated in two types of congenital nephrotic syndrome, was pivotal in establishing the podocyte as the central component of the glomerular filtration barrier. In vivo the proteins have been localized to the podocyte slit diaphragm, and there is recent evidence for interaction between the two via the adapter molecule CD2AP. We describe in a human podocyte cell line, the subcellular distribution of nephrin, podocins, and CD2AP and their functional interaction with the cytoskeleton. In addition to membrane expression, nephrin and podocin were detected intracellularly in a filamentous pattern. Double immunolabeling and depolymerization studies showed that nephrin and podocin partially co-localize with actin, most strikingly seen protruding from the tips of actin filaments, and are dependent on intact actin polymers for their intracellular distribution. Treatment of differentiated podocytes with puromycin aminonucleoside, an agent that causes foot process effacement in vivo, disrupted actin and nephrin simultaneously, with loss of cell surface localization. We demonstrate an intimate relationship between nephrin podocin and filamentous actin, and reason that disruption of nephrin/podocin could be a final common pathway leading to foot process effacement in proteinuric diseases.

Actins↗
PubMed2002

Human podocytes express angiopoietin 1, a potential regulator of glomerular vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is abundantly expressed by podocytes, but its role in glomeruli is unknown. Angiopoietins are endothelial cell growth factors that function in concert with VEGF but have not previously been observed in human glomeruli. Angiopoietin 1 (Ang1) acts via the endothelial receptor Tie2 to promote maturation and stabilization of blood vessels, resisting angiogenesis and opposing some actions of VEGF. Ang1, Ang2, Tie2, and VEGF expression in normal human renal cortex was examined with immunofluorescence and immunohistochemical analyses. High-power, multiple-color, immunofluorescence analyses and additional antibodies (specific for particular components of the glomerular filtration barrier) were used to determine the exact locations of Ang1 and Tie2 in the glomerular capillary wall. Immuno-electron-microscopic analysis of rat glomeruli was used to further localize endothelial Tie2 expression. RNA and protein extracted from human glomeruli, cultured human podocytes, and cultured human endothelial cells were analyzed for Ang1, Ang2, and Tie2 by using reverse transcription-PCR and Western blotting. Ang1 was detected in podocytes in normal glomeruli and, with VEGF, was concentrated in podocyte foot processes. Tie2 was demonstrated on glomerular capillary endothelial cells, particularly on the abluminal surface. Reverse transcription-PCR and Western blotting analyses confirmed the expression of Ang1 and Tie2 in glomeruli and of Ang1 in cultured podocytes. These findings suggest a role for Ang1 in the maintenance of the glomerular endothelium and make it a good candidate to be a regulator of the actions of VEGF on glomerular permeability, resisting angiogenesis while allowing the induction of high permeability to water and small solutes.

Angiopoietin-1↗
PubMed2002

A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression.

Recent molecular insights have established the podocyte as a key component of the glomerular filtration barrier, and hence an important common pathway in proteinuric diseases. A conditionally immortalized human podocyte cell line has been developed by transfection with the temperature-sensitive SV40-T gene. These cells proliferate at the "permissive" temperature (33 degrees C). After transfer to the "nonpermissive" temperature (37 degrees C), they entered growth arrest and expressed markers of differentiated in vivo podocytes, including the novel podocyte proteins, nephrin, podocin, CD2AP, and synaptopodin, and known molecules of the slit diaphragm ZO-1, alpha-, beta-, and gamma-catenin and P-cadherin. The differentiation was accompanied by a growth arrest and the upregulation of cyclin-dependent kinase inhibitors, p27 and p57, as well as cyclin D(1), whereas cyclin A was downregulated. These data are consistent with cell cycle protein expression during podocyte maturation in vivo. In conclusion, the development of this cell line provides a new tool in the study of podocyte biology, which will enable accurate assessment of the behavior of these complex cells in health and disease.

Biomarkers↗
PubMedDate not supplied

Glomerulonephritis: is it worth worrying about?

Glomerulonephritis (GN) is a group of conditions characterised by inflammation in the filtering units of the kidney which may be 'primary'; secondary to drugs, infections or tumours; or the presenting feature of systemic disease. GN is treatable, causes significant morbidity and mortality, and is a potentially preventable cause of renal failure and cardiovascular risk. It can only be precisely identified and characterised by renal biopsy which is usually undertaken in specialist nephrology centres. The role of the non-specialist is to know when and how urgently a patient should be referred to such a centre. This review aims to provide guidance on when to suspect GN, how to investigate this possibility and when to refer for further investigation. Clinically urgent situations are highlighted. The importance of urinary abnormalities, particularly proteinuria (even if aysmptomatic and only detected on routine screening) is emphasised. Earlier recognition of GN will improve patient outcomes.

Biopsy↗
PubMedDate not supplied

Angiopoietins: microvascular modulators with potential roles in glomerular pathophysiology.

Angiopoietins are a recently discovered family of growth factors which act on endothelial cells via Tie receptors. They are widely expressed and have essential roles in regulating vascular growth, development, maturation and permeability. Disturbances in microvascular regulation play an important part in a number of diseases prominent in the developed world including diabetes, ischemic heart disease and cancer. It is the interplay between angiopoietins and other factors including vascular endothelial growth factor (VEGF) which determines endothelial behavior both in health and in these diseases. Angiopoietin-1 is unique in its ability to reduce endothelial permeability and it antagonises the effects of VEGF in its permeability and angiogenesis-inducing actions. The renal glomerulus constitutes a highly specialized microcirculation in which the permeability characteristics of the capillary wall allow its unique filtration function. Disturbance of this function may cause a reduction in glomerular filtration rate or proteinuria. Understanding of the regulation of the filtration barrier is incomplete but the expression of angiopoietins in the glomerulus suggests a mechanism for maintenance of the glomerular endothelium and modulation of the actions of glomerular VEGF. As has been clearly shown for VEGF, angiopoietins are likely to be involved in glomerular disease and recovery from it. Manipulation of angiopoietins has a wide range of potential therapeutic applications from inhibition of diabetic retinal neovascularisation to promotion of glomerular repair.

Angiogenesis Inducing Agents↗